This application is a 371 of PCT/BP99/08135 filed of Oct. 11, 1999.
This invention relates to novel processes for preparing intermediates (particuiarly 4-cyano-3-nitrobenzotrifluoride) useful in the preparation of pesticides.
Pesticidal 4-benzolisoxazoles, particularly 5-cyclopropylisoxazole herbicides and intermediate compounds in their synthesis, are described in the literature, for example in European Patent Publication Nos. 0418175, 0487353, 0527036, 0560482, 0609798 and 0682659.
Various methods for preparing these compounds are known. The present invention seeks to provide improved methods for the preparation of pesticides and the intermediate compounds useful in preparing them.
It is therefore an object of the present invention to provide novel and more economical processes for the preparation of ortho-nitrobenzonitrile compounds.
It is a further object of the present invention to provide processes for the preparation of ortho-nitrobenzonitrile compounds which proceed in high yield and/or with high selectivity.
It is a further object of the present invention to provide a process for the preparation of ortho-nitrobenzonitrile compounds which requires a low amount of copper compound as catalyst.
It is a further object of the present invention to provide a process for the preparation of ortho-nitrobenzonitrile compounds which proceeds using cuprous cyanide without the need for a catalyst.
It is a further object of the present invention to provide a process for the preparation of ortho-nitrobenzonitrile compounds which proceeds at a lower temperature than known methods and therefore easier to perform.
The present invention allows these objects to be met in whole or in part.
The present invention accordingly provides a process for the preparation of an ortho-nitrobenzonitrile compound of formula (I): 
wherein:
R1 represents C1-4 haloalkyl (preferably trifluoromethyl), fluorine, chlorine or bromine; and R2 represents hydrogen or C1-4 alkoxy; which process comprises the reaction of the corresponding ortho-nitrohalobenzene of formula (II): 
wherein R1 and R2 are as hereinbefore defined and X represents a fluorine, chlorine or bromine atom, with when X represents a flourine atom:
a) an alkali metal cyanide, in a non aqueous solvent optionally in the presence of a catalyst; or
when X represents a chlorine atom:
(b) cuprous cyanide and a source of bromide selected from hydrogen bromide, bromine and a tetraalkylammonium bromide; optionally in the presence of an alkali metal bromide or an alkaline earth metal bromide; or
(c) an alkali metal cyanide or a tetraalkylammonium cyanide, in the presence of cuprous bromide and a phase transfer catalyst; or
(d) cuprous cyanide and lithium iodide; or
when X represents a bromine atom:
(e) cuprous cyanide optionally in the presence of a catalyst selected from an alkali metal bromide or an alkaline earth metal bromide; or
(f) an alkali metal cyanide in the presence of a catalytic amount of cuprous cyanide and a phase transfer catalyst.
Certain compounds of formula (I) are known and a number of processes for their preparation and conversion into herbicidal 4-benzoylisoxazole derivatives have been described in the European Patent Applications cited above.
Compounds of formula (II) are known or may be prepared by known methods.
In formulae (I) and (II) and in the formulae depicted hereinafter, preferred values of the symbols are as follows:
Preferably R1 represents trifluoromethyl, fluorine or bromine; and R2 represents hydrogen or methoxy.
In a particularly preferred embodiment of the invention R1 represents trifluoromethyl and R2 represents hydrogen.
It is to be understood that in this invention the term xe2x80x9calkylxe2x80x9d which forms part of tetralkylammonium salts represents a straight-or branched-chain alkyl group containing from one to six carbon atoms.
The above preparation a) of compounds of formula (I) from compounds of formula (II) wherein X represents a fluorine atom is performed with an alkali metal cyanide (for example sodium cyanide or potassium cyanide). Sodium cyanide is preferred. The amount of cyanide used is generally from 1-2 molar equivalents, preferably from 1-1.1 molar equivalents.
A number of non-aqueous solvents are suitable, for example nitrites such as acetonitrile or benzonitrile; ethers such as tetrahydrofuran or diglyme (diethylene glycol dimethyl ether); amides such as N,N-dimethylformamide or N-methylpyrrolidone; ketones such as methyl isobutyl ketone; esters such as methyl benzoate or n-butyl acetate; dimethylsulphoxide or sulpholane. Preferably the solvent is chosen from benzonitrile, acetonitrile, tetrahydrofuran or N,N-dimethylformamide.
The reaction is generally conducted in a solvent with less than about 1% by volume water content preferably less than about 0.5%, even more preferably less than about 0.1%, typically from about 0.005 to about 0.05%. It will however be understood that in certain cases slightly more or less water may be tolerated, depending on the nature of the solvents used and the temperature of the reaction, the compound of formula (I) to be prepared and other reaction conditions.
Preferably a catalyst is used, which may be selected from ammonium salts (such as tetraalkylammonium or trialkylbenzylammonium chlorides, bromides or hydrogen sulphate salts, in which the alkyl groups are straight- or branched-chain containing from one to six carbon atoms, such as tetramethylammonium bromide); or preferably guanidinium salts (such as hexabutylguanidinium chloride or hexamethylguanidinium chloride). The amount of catalyst when employed is generally from 0.01 to 0.3 molar equivalent, preferably from 0.05-0.25 molar equivalent.
Generally the reaction temperature is from 20xc2x0 C. to the boiling point of the solvent, preferably from 30xc2x0 C. to 180xc2x0 C., and more preferably from 60xc2x0 C. to 100xc2x0 C.
The above preparation (b) of compounds of formula (I) from compounds of formula (II) wherein X represents a chlorine atom is performed with cuprous cyanide and a source of bromide selected from hydrogen bromide, bromine and a tetraalkylammonium bromide, optionally in the presence of an alkali metal bromide or an alkaline earth metal bromide, preferably lithium bromide. In this process the amount of cuprous cyanide used is generally from 0.5-2 molar equivalents and preferably from 0.8-1.2 molar equivalents.
The amount of bromide source used is generally from 0.05-1 molar equivalent.
When an alkali metal bromide or an alkaline earth metal bromide is also present in the reaction mixture it is used in catalytic amount, generally from 0.01-0.5 molar equivalents and preferably from 0.02-0.05 molar equivalents.
The solvent may be chosen from nitrites such as acetonitrile or benzonitrile; ketones such as methyl isobutyl ketone; ethers such as tetrahydrofuran or diglyme (diethylene glycol dimethyl ether); esters such as methyl benzoate or n-butyl acetate; dimethylsulphoxide or sulpholane. Preferred solvents are acetonitrile, benzonitrile or diglyme.
The concentration of the compound of formula (II) used in the reaction solvent is generally in the range from 0.1 ml/mmol to 2 ml/mmol, and preferably from 0.2 ml/mmol to 1 ml/mmol.
The reaction temperature is generally from 100xc2x0 C. to 200xc2x0 C., preferably from 130xc2x0 C. to 180xc2x0 C.
The above preparation (c) of compounds of formula (I) from compounds of formula (II) wherein X represents a chlorine atom is performed with an alkali metal cyanide (for example sodium cyanide or potassium cyanide) or a tetraalkylammonium cyanide, in the presence of cuprous bromide and a phase transfer catalyst.
Preferably the alkali metal cyanide is potassium cyanide. The amount of alkali metal cyanide or tetraalkylammonium cyanide used is generally 1-1.5 molar equivalents (preferably 1-1.1 molar equivalents. The amount of cuprous bromide used is generally from 0.01-2 molar equivalents (preferably 1 molar equivalent). The reaction is conducted using solid liquid phase transfer catalysis. The phase transfer catalyst may be selected from tetraalkylammonium salts or trialkylbenzylammonium salts (such as tetramethylammonium bromide or benzyltrimethylammonium bromide); phosphonium salts (such as tributylhexadecylphosphonium bromide); guanidinium salts (such as hexabutylguaridinium bromide or hexamethylguanidinium bromide); and crown ethers (such as 18-crown-6). The amount of phase transfer catalyst used is generally from 0.05-0.3 molar equivalents. Suitable solvents for the reaction include nitriles such as acetonitrile or benzonitrile; ethers such as tetrahydrofuran or diglyme (diethylene glycol dimethyl ether); ketones such as methyl isobutyl ketone; or esters such as methyl benzoate. The preferred solvent is acetonitrile.
The concentration of the compound of formula (II) used in the reaction solvent is generally in the range from 0.1 ml/mmol to 2 ml/mmol, and preferably from 0.2 ml/mmol to 1 ml/mmol.
The reaction temperature is generally from 100xc2x0 C. to 200xc2x0 C., preferably from 130xc2x0 C. to 180xc2x0 C.
The above preparation (d) of compounds of formula (I) from compounds of formula (II) wherein X represents a chlorine atom is performed using cuprous cyanide and lithium iodide. Generally from 0.5-2 molar equivalents (preferably from 0.8-1.2 molar equivalents) of cuprous cyanide is employed in the reaction. The amount of lithium iodide employed is generally from 0.05 to 2 molar equivalents, preferably from 0.2 to 0.5 molar equivalents.
Suitable solvents for the reaction include nitrites such as benzonitrile or acetonitrile; ethers such as diglyme (diethylene glycol dimethyl ether); ketones such as methyl isobutyl ketone; or esters such as methyl benzoate.
The reaction temperature is generally from 100xc2x0 C. to 200xc2x0 C., preferably from 130xc2x0 C. to 180xc2x0 C.
The above preparation (e) of compounds of formula (I) from compounds of formula (II) wherein X represents a bromine atom is performed using cuprous cyanide optionally in the presence of a catalyst selected from an alkali metal bromide or an alkaline earth metal bromide, preferably lithium bromide. Generally from 0.5-2 molar equivalents (preferably 1-1.1 molar equivalents) of cuprous cyanide is employed in the reaction. The amount of catalyst employed (when present) is generally from 0.05 to 2 molar equivalents.
Suitable solvents for the reaction include nitrites such as acetonitrile or benzonitrile; ethers such as tetrahydrofuran or diglyme (diethylene glycol dimethyl ether); ketones such as methyl isobutyl ketone; esters such as methyl benzoate or n-butyl acetate; amides such as N,N-dimethylformamide or N-methylpyrrolidone; dimethylsulphoxide or sulpholane. Preferred solvents are acetonitrile, benzonitrile or tetrahydrofuran.
The reaction temperature is generally from 100xc2x0 C. to 200xc2x0 C., preferably from 110xc2x0 C. to 160xc2x0 C. (more preferably 120xc2x0 C. to 140xc2x0 C.).
The compound of formula (II) used in the reaction may contain a proportion (generally up to 20%) of the corresponding compound in which the bromine atom is replaced by a chlorine atom. It has been found that this is not detrimental to the reaction. It may therefore be more convenient or straightforward to purify and isolate the nitrile compound of formula (I) rather than using a pure compound of formula (II). This separation may be achieved by standard procedures known in the art, for example by distillation.
The above preparation (f) of compounds of formula (I) from compounds of formula (II) wherein X represents a bromine atom is performed using an alkali metal cyanide in the presence of a catalytic amount of cuprous cyanide and a phase transfer catalyst. Potassium cyanide is the preferred alkali metal cyanide. The amount of cuprous cyanide used is generally from 0.05 to 0.2 molar equivalents. The amount of alkali metal cyanide used is generally from 0.5-2 molar equivalents, preferably from 0.6-1.3 molar equivalents (more preferably 0.7-1 molar equivalents). The phase transfer catalyst may be selected from alkali metal bromides or alkaline earth metal bromides, preferably lithium bromide; tetraalkylammonium bromides or trialkylbenzylammonium bromides, in which the alkyl groups are straight- or branched-chain containing from one to six carbon atoms (such as tetramethylammonium bromide or benzyltrimethylammonium bromide); phosphonium salts (such as tributylhexadecylphosphonium bromide); guanidinium salts such as (hexabutylguanidinium bromide or hexamethylguanidinuim bromede); and crown ethers (such as 18-crown-6). The amount of phase transfer catalyst used is generally from 0.05-0.5 molar equivalents (preferably from 0.05-0.3 molar equivalents.
Suitable solvents for the reaction include nitriles such as acetonitrile or benzonitrile; alcohols such as n-butanol; amides such as N,N-dimethylformamide or N-methylpyrrolidone; ketones such as methyl isobutyl ketone; esters such as methyl benzoate; ethers such as tetrahydrofuran or diglyme (diethylene glycol dimethyl ether) dimethylsulphoxide or sulpholane.
The concentration of the compound of formula (II) used in the reaction solvent is generally in the range from 0.1 ml/mmol to 2 ml/mmol, preferably from 0.2 ml/mmol to 1 ml/mmol, more preferably from 0.2 ml/mmol to 0.4 ml/mmol.
The reaction temperature is generally from 100xc2x0 C. to 200xc2x0 C., preferably from 110xc2x0 C. to 160xc2x0 C.
According to a further feature of the present invention there is provided a process (g) for the preparation of a compound of formula (II) wherein R1 and R2 are as hereinbefore defined and X represents a bromine atom, which comprises the reaction of the corresponding compound of formula (II) in which X represents a chlorine atom, with a bromide source.
Examples of suitable bromide sources include alkali metal bromides (such as potassium bromide or lithium bromide); alkaline earth metal bromides (such as magnesium bromide); cuprous bromide; cupric bromide; zinc bromide; hydrogen bromide; or bromine; or a mixture of lithium bromide and cuprous bromide. The preferred bromide source is a mixture of lithium bromide and cuprous bromide; or magnesium bromide or cupric bromide. The amount of bromide source used is generally one to five molar equivalents. When a mixture of lithium bromide and cuprous bromide is used, 0.1-1 molar equivalents of cuprous bromide is generally employed, together with one to two molar equivalents of lithium bromide.
A solvent is generally required to obtain good results. Suitable solvents for the reaction include nitrites such as acetonitrile or benzonitrile; ethers such as tetrahydrofuran or diglyme (diethylene glycol dimethyl ether); ketones such as methyl isobutyl ketone; esters such as methyl benzoate or n-butyl acetate; N-methylpyrrolidone; alkanoic acids such as acetic acid; dimethylsulphoxide and sulpholane.
The reaction temperature is generally from 100xc2x0 C. to 200xc2x0 C., preferably from 130xc2x0 C. to 180xc2x0 C. Good results are obtained when the process is carried out in a concentrated medium.
According to a further feature of the present invention processes (e) or (f) can be combined with process (g) to prepare a compound of formula (I) starting from a compound of formula (II) wherein X represents a chlorine atom.
The compounds of formula (I) obtained by the processes of the present invention may be used in the preparation of herbicidally active 4-benzoylisoxazole derivatives for example according to the following reaction scheme: 
The 4-benzoylisoxazoles of formula (III) are described in for example European Patent Publication Nos. 0418175, 0527036 and 0560482.